Traumatic brain injury and pathophysiologic consequences of the traumatic brain injury have been theorized by several mechanisms such as ‘positive pressure theory’, ‘rotational shear stress theory’, ‘angular acceleration theory’, ‘cerebrospinal fluid displacement theory’ and ‘negative pressure theory resulting in cavitation’. These theories, however, have failed to conclusively verify unifying mechanisms of the traumatic brain injury of the so-called contrecoup injury and other associated injuries. Researches have begun investigating cases of chronic traumatic encephalopathy sustained by combat soldiers and athletes for pathophysiologic changes in cellular and molecular levels using mouse or porcine models. Diffuse axonal injury and cerebral vasospasm without bleeding from cerebral blood vessels have been identified as one of pathophysiologic changes after the blunt head trauma. Integrin mediated activation of Rho kinase and phenotypic switches indicative of vascular remodeling have also been identified. In addition, computer simulations of the blunt head trauma using finite element models have advanced our understanding of mechanisms of the traumatic brain injury. Of note, all of these studies have been based on and postulated by level of macroscopic deformation of a brain tissue and changes in intracranial pressure upon the traumatic brain injury. Tissue injury such as axonal injury is presumed to occur once a certain tolerance limit of either the deformation or the intracranial pressure of the brain tissue is exceeded. For example, estimates of the shear strains in volunteers during physiological rotations of brain have been shown to reach near the thresholds for axonal damage at 0.05 mm/mm.
Tissue damage could also occur by repetitive vibrations of the tissue from mechanical waves without increases in pressure the tissue is under or measurable deformations of the tissue by an accelerating or decelerating mechanical force. One example of this phenomenon has been clinically used for breaking up kidney stones of patients by delivering shock waves which are mechanical waves. Complications of the shock wave therapy (Lithotripsy) include intraparenchymal and perirenal hemorrhage and edema as acute complications and loss of renal function and hypertension as chronic complications, indicating that the shock waves can damage soft tissues of the kidney which do not come under deformation of their structure nor increase in their tissue pressure upon an exposure to the shock waves. Separately, studies on vascular damage and disorder of bone formation by repetitive vibrations imply that the vibrations of the mechanical waves to tissue should also be considered a factor of the tissue damage. For the traumatic brain injury which is a result of a blunt trauma delivering the mechanical waves having a certain set of frequency and amplitude to a brain, there have not been well studied correlative data on the frequency and the amplitude of the mechanical waves with pathophysiologic findings for individual tissues of the brain upon the blunt trauma. It appears that common reasons for lack of the data come not only from our inability to obtain such data from the experimental brain models, but also from lack of such consideration for mathematical algorithms for computational simulations using the finite elements which are currently available. The mathematical algorithms for the computational simulations have relied on theoretical hypotheses of the tissue damage by development of the deformation of the tissue and increases in the intracranial pressure. There has not been a theoretical exercise to answer a hypothetical question on “Will there be a tissue damage upon the blunt trauma if there is no macroscopically measurable deformation nor an increase in intracranial pressure?”. Deciphering quantitative correlation between the frequency and the amplitude of the mechanical waves and the pathophysiologic changes of the brain will surely positively advance our understanding of the traumatic brain injury and our designing protective headgears against the traumatic brain injury.
Instrumentation with pressure sensors and accelerometers directly attached to a portion of an experimental model of a brain may interfere with unmodified propagation of the mechanical waves through the brain model, since the pressure sensors and the accelerometers serve as a boundary having a different transfer function to the mechanical waves crisscrossing the brain model. The pressure sensors and the accelerometers comprise a printed circuit board and electronic components, which are heterogeneous and different in composition of materials from materials of the brain model. Even when these sensors could be placed on an outer surface of the brain model, there would be mechanical waves bouncing off the sensors in a different way from what is expected in the unmodified propagation of the mechanical waves through the brain model. For this reason, it would be better in understanding kinetic response of the brain model to use non-contact measurement methods of the mechanical waves and the deformation of the brain model upon the blunt trauma.
Laser doppler vibrometry allows non-contact measurement of frequency and amplitude of mechanical vibrations of an object in a wide range of frequency with a resolution of a subnanometer. A three-dimensional conformational modeling of a brain of the present invention comprises a skull base on which three structurally distinct components sit, including cerebrum, brain stem and cerebellum. An undersurface of a frontal lobe and an undersurface of occipital lobe of the cerebrum can be exposed if the brain is positioned upside down with a skull overlying the brain being vertically below the brain and the skull base eliminated. A single point laser doppler vibrometer such as Polytec OFV-55x with OFV-2570 (Polytec GmbH Waldbronn) can be configured to aim at a point of the undersurface of the frontal lobe, which can measure the frequency and the amplitude of the mechanical waves of a blunt trauma to the skull transmitted to the frontal lobe. Likewise, another laser doppler vibrometer aims at a point of the undersurface of the occipital lobe. Furthermore, a scanning laser vibrometer such as PSV-500-3D Scanning Vibrometer (Polytec GmbH Waldbronn) can obtain data of frequencies and amplitudes of an entire area of the undersurface of the both frontal and occipital lobes.
A major obstacle of our understanding of mechanical changes of the brain upon the traumatic brain injury is our inability to see inner components of the brain following the blunt trauma. Magnetic resonant imaging (MRI) studies have been utilized for visualization of the inner components but it has been limited by low resolution, slow image acquisition rate and requirement of an elaborate equipment. Non-infrared (NIR) fluorescence with excitation >750 nm can be utilized for assessing displacement of inner components of a three-dimensional conformational brain model based on its high signal-to-noise ratio, minimal light absorption, maximal penetration, and low background due to minimal autofluorescence. A source of a primary NIR light is placed in the middle of the three-dimensional conformational brain model, which provides a high-intensity NIR light of >750 nm in a spherical distribution to cover the three-dimensional conformational brain model. The three-dimensional conformational brain model comprises NIR fluorophore beads orderly dispersed inside the brain model, which has a maximum absorption of NIR of >750 nm. A secondary NIR light is emitted from the NIR fluorophore beads upon excitation by the primary NIR light through the three-dimensional conformational brain model to the exposed surface of a base portion of the three-dimensional conformational brain model, which is configured to be detected by an NIR imaging camera installed away from the three-dimensional conformational brain model for non-contact imaging of the three-dimensional conformational brain model. The NIR camera would be high-speed and high-resolution, like High definition Mini SWIR™ (Sensors Unlimited, UTC Aerospace Systems) which has a 640×512 pixel InGaAs camera capable of 109 full frames per second with frame rates over 15,220 full frames per second depending on the selected pixel area.
The three-dimensional conformational brain model is configured to imitate gyral convolutions and sulci noted on a surface of a human brain. An apical portion of the gyri along a longitudinal line and a valley portion of the sulci along a longitudinal line are imprinted with a linear radiopaque thermoplastic or a thin metal strip, which can be visualized by a digital X-ray fluoroscope using a high-speed and high-resolution complimentary metal-oxide semiconductor (CMOS) detector such as Dexela 2307 flat panel X-ray detector (PerkinElmer Inc.) featuring a 3072×864 pixel matrix and up to 191 frame per second visualization. The fluoroscopic image captures movements of radiopaque lines on the gyri and in the sulci reflecting movements of a spherical surface of the three-dimensional conformational brain model, whereas the NIR image discloses internal displacement of the three-dimensional conformational brain model. These two imaging modalities are coordinated in real time with the laser doppler vibrometer for recording structural changes, and a frequency and an amplitude of the vibration of the three-dimensional conformational brain model upon the blunt trauma.
One key consideration for modeling a model brain for experimentation for the traumatic brain injury is a composition of materials which should mimic the composition of natural brain. Whole brain comprises water of 75˜80%, fat of 10%, cerebroside of 2% and protein of 8%. Gray matter of the brain comprises water of 83%, fat of 5%, cerebroside of 1% and protein of 7.5%. White matter of the brain comprises water of 70%, fat of 10.5%, cerebroside of 4.5% and protein of 8.5%. Cerebrospinal fluid has up to about 40 mg/dL of protein and a negligible amount of sugar. Differences in the composition between the gray and white matters are most significant for their water concentration, which has an implication of differences on the transfer function for transmission of mechanical waves through each matter and of the boundary effect of the mechanical waves. Furthermore, the gray matter comprises mostly neuronal cells having a round cellular body whereas the white matter has striated, relatively linear axons spreading out from the neuronal cells, which would affect propagation of the mechanical waves differently through each matter. Apart from the finite element models for computer simulations, existing models using polymers such as gelatin, Sylgard elastomer, polydimethylsiloxane-based (PDMS) gels, or agarose gel do nor reflect these differences nor do they contain a water concentration up to 80% except for the gelatin and the agarose gel.
A suitable material for the model brain for experimentation for the traumatic brain injury would require a significant amount of water up to 85% embedded in a polymeric cross-linking structure, to share elastomeric properties similar to that of the brain and to be chemically inert. Limitations for the gelatin and the agarose gel are that they are denatured biological materials which get decomposed over time, resulting in a decay of their original elasticity and a potential problem of inconsistency in test results due to their change in conformation over time, and a limited shelf life. One major advantage of the gelatin and agarose gel is that they are heterogeneous in size with varying molecular weight, mimicking the natural brain comprising diverse components with a wide range of molecular weights. In contrast, synthetic hydrophilic polymers such as polyacrylamide, or poly(2-hydroxyethyl methacrylate) are relatively homogeneous, have a more refined range of molecular weight, are stable over an extended period of time, and yield consistently reproducible test results. Both organic gels and synthetic hydrophilic polymers can be used for the model brain for the present invention, tailored for their advantages and limitations.
For visualization of internal deformation of the model brain upon the traumatic brain injury, the hydrophilic polymer of the model brain in a three-dimensional configuration can be marked with orderly arranged NIR dye beads which emit light in an NIR spectrum upon an incident NIR light. For an example, NIR dye beads are made of a poly(N-vinyl imadazole) polymer which is both water soluble and methanol soluble. A range of solvent soluble NIR dyes such as ADS775MI (2-[2-[2-Chloro-3-[(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)ethylidene]-1-cycloxen-1-yl]-ethenyl]-1,3,3-trimethyl-1H indolium iodide) (American Dye Source, Inc) can be incorporated into the poly(N-vinyl imadazole) NIR beads in a methanol solvent. As the poly(N-vinyl imadazole) NIR beads are water soluble, they can be statically incorporated into the hydrophilic polymer of the model brain containing water molecules. The ADS775MI associated with the poly(N-vinyl imadazole) NIR beads remains only in the poly(N-vinyl imadazole) NIR beads, and does not leak out to a surrounding hydrophilic polymer of the model brain, since it is methanol soluble but not water soluble. A source of NIR light is placed close to a middle of the three dimensional conformation of the model brain and is configured to generate an intensity of NIR light enough to penetrate entire hydrophilic polymeric layers of the model brain in a way an emitted NIR light from the poly(N-vinyl imadazole) NIR beads reaches to a surface of the model brain with a sufficient intensity to be detected by an NIR camera placed away from the model brain in a distance. The emitted NIR light from the NIR beads will be seen by the NIR camera in a pattern similar to a shaded topographic map of a region by a geostationary satellite scanning the region. If there would be a temporary internal deformation or structural changes of the hydrophilic polymer of the model brain upon the blunt trauma, there will be fluctuating areas of a higher density of the emitted NIR light and of a lower density of the emitted NIR light which can be captured in real time following reception of the blunt trauma by the NIR camera configured to visualize the changes in the distribution of the orderly dispersed NIR beads into aggregated clusters of the NIR beads in the three-dimensional conformational model brain.
The three-dimensional conformational model brain can be divided into nine distinctive geometric groups which would respond to the mechanical waves of the blunt trauma differently from each other. These include an opposing pair of one-half cerebral hemispheres, a pair of free ended temporal lobes having an elongated trapezoidal configuration located below the one-half cerebral hemispheres, a pair of occipital lobes which adjoin a distal part of each temporal lobe and are located distal to the one-half cerebral hemispheres, a corpus callosum in a box configuration adjoining a medial surface of each one-half cerebral hemisphere and a brain stem in a cylindrical configuration adjoining the corpus callosum. In addition, a cerebellum in a configuration of a ellipsoidal disk can be reversibly combined with a distal part of a portion of the brain stem. Although these parts are interconnected with each other, they are configured to be freely movable on their own simulating a natural state of a natural brain. It is important to recognize that the brain comprises a group of freely movable parts independent of each other, albeit in a tight space, which is not reflected by all available finite element models for computer simulations. Furthermore, in a natural brain, the cerebellum is separated from the cerebrum and its associated structures by a tout tentorial membrane which segregates the cerebrum into a supratentorial region and the cerebellum into a infratentorial region of the brain. Importance of the tentorial membrane cannot be ignored as herniation of the cerebrum and its associated structure through a hole of the tentorial membrane from the supratentorial region to the infratentorial region results in death for almost all individuals. Mechanistically, presence or absence of the cerebellum in the model brain would alter kinetic response of the model brain upon the blunt trauma. Therefore, two separate models of the model brain would be necessary for studying the traumatic brain injury, with one with the cerebellum and the other without the cerebellum. The model brain with the cerebellum is designed to study a kinetic response of an entire brain structure of the model brain, whereas the model brain without the cerebellum focuses on a kinetic response of the supratentorial region of the model brain.
Cerebrospinal fluid (CSF) serves as a liquid medium which facilitates transfer of various components in the brain and contributes to homeostasis of the brain. In the traumatic brain injury, role of the CSF is yet undefined. Although there are speculative descriptions on a protective role of the CSF for the brain, none of these are based on solid investigative findings except for its role for neutral buoyancy for the brain to maintain a suspended configuration inside the meningeal membrane. All internal organs such as heart, lungs and bowel are immersed in a tiny amount of a biologic fluid which serves for important roles for the transfer of biologic materials between the organs, surveillance of foreign antigens, and maintenance of homeostasis of the organs. It stands to reason that the CSF is no exception to this and there would not be a mechanical role of the CSF for protecting the brain in case of the blunt trauma. In the kinetic response to the blunt trauma, the CSF may rather serve as a simple fluid medium having a higher transfer function for the mechanical waves of the blunt trauma to the brain facilitating transfer of the frequency and the amplitude of the mechanical waves to the brain proper. To investigate the role of the CSF for the traumatic brain injury, the three-dimensional conformational model brain comprises two separate configurations for a CSF sac. One model has a fully encapsulated configuration of the model brain for its entirety including all nine geometric groups except for a distal part of the brain stem. A second model has an open configuration which lacks a basal membrane of the CSF sac covering the base portion of the model brain. A bowl shaped hemispherical portion of the CSF sac covers a top portion of the cerebral hemisphere, while a bottom portion of the model brain is exposed. The exposed bottom portion of the model brain can be assessed by the laser doppler vibrometer for studying vibration of the model brain per se. The first model with full encapsulation of the model brain can also be studied for the vibration by the laser doppler vibrometer. In the first model, the membrane portion of the CSF sac covering the bottom portion of the model brain will be assessed for the vibration.
Intensity of an amplitude of the mechanical waves delivered to the brain tissue depends on a mass (weight) of a source generating the mechanical waves multiplied by a velocity of an impact from the source and a mass (weight) of a victim and a stopping distance of the impact by the victim colliding with the source: KE=½×mv2 where KE is kinetic energy before an impact, m is mass in kg and v is velocity in meter/second. Since the stopping distance of the impact by the victim is a relatively fixed value, the weight of both the source and victim for the most part would determine the amplitude of the mechanical waves from the impact. This can be studied by having a colliding dummy which varies in weight and impact velocity, while the model brain is harnessed by a positioning device in a standstill. The colliding dummy is driven to collide the model brain at an angle, simulating common situations of the blunt trauma. Since the blunt trauma is a bidirectional event involving both the colliding dummy and the model brain, data on gravitational force, impact pressure, translational displacement and rotational displacement of the impact between the colliding dummy and the model brain can be obtained by a pressure sensor and a triaxial accelerometer placed within a head portion of the colliding dummy.